According to Outline of Results from 2007 National Health and Nutrition Survey published by the Ministry of Health, Labour and Welfare, it is estimated that there are approximately 8.9 million people who are “strongly suspected of having diabetes” and approximately 13.2 million people who are “likely to have diabetes” in Japan. That is to say, it is predicted that a total of approximately 22.1 million Japanese people are affected with or are likely to have diabetes. Diabetes is defined as a state of chronic hyperglycemia caused by impaired insulin action. Insulin is secreted from pancreatic β-cells and acts on organs on which insulin acts, such as liver or skeletal muscle. As a result of such insulin action, glucose uptake and suppression of gluconeogenesis are induced in the liver, and glucose uptake is induced in the skeletal muscle. However, if reduction in insulin secretion and/or insulin resistance are provoked by a certain reason, impaired insulin action occurs, and the normoglycemic state changes to a hyperglycemic state, thereby resulting in the onset of diabetes. There is a fear that diabetes may increase the risk of developing diabetic nephropathy, retinopathy, nervous disorder, and great vessel disorder, and that it may further lead to a significant reduction in quality of life (QOL), such as the necessity of dialysis, blindness, quadruple amputation, arteriosclerotic disease and stroke.
For the treatment of diabetes, kinesitherapy, dietetic therapy, and drug therapy are carried out. Examples of agents used in drug therapy include agents for promoting insulin secretion from pancreatic β-cells, agents for improving insulin resistance, agents for suppressing glucose absorption, and agents for promoting the use of glucose. Among these agents, since insulin secretagogues are expected to increase blood insulin level and lower blood glucose level, they are anticipated to suppress hyperglycemia and improve diabetes. A sulfonyl urea preparation (SU drug), a short acting insulin secretagogue, a DPPIV inhibitor (see non-patent document 1), a GLP-1 analog (see non-patent document 2) and the like have been practically used in the clinical setting of treating diabetes. However, the SU drug, which has been most frequently used in Japan and stimulates pancreatic β-cells and promotes endogenous insulin secretion (see non-patent document 3), may cause hypoglycemia as a side effect. Thus, attention should be paid when this drug is used, in particular, for elder people, people with deterioration of renal function, and in the case of an irregular dietary habit. In addition, with regard to the SU drug, side effects such as an increase in body weight have also been reported. Moreover, the SU drug has been known to cause primary failure in which no effects are found from an initial administration, or secondary failure in which clinical effects disappear during the administration period.
Glucokinase (hereinafter also abbreviated as “GK”) belongs to a hexokinase family and has an alias “hexokinase IV.” Hexokinase is an enzyme that catalyzes conversion of glucose to glucose-6-phosphate at an initial stage of the glycolysis system in a cell. In the case of three hexokinases other than GK, enzymatic activity becomes saturated at a glucose level of 1 mmol/L or less. On the other hand, GK has low affinity for glucose and shows a Km value close to a physiological blood glucose level (8 to 15 mmol/L). GK is mainly expressed in liver and pancreatic β-cells. In recent years, it has been elucidated that GK is also present in brain. The sequences of N-terminal 15 amino acids are different between GK in the liver and GK in pancreatic β-cells, depending on a difference in splicing. However, they have identical enzymatic properties, and intracellular glucose metabolism via GK is accelerated in response to a change in blood glucose levels from a normal blood glucose level (around 5 mM) to postprandial hyperglycemia (10 to 15 mmol/L).
Through the ages, a hypothesis had been proposed that GK functions as a glucose sensor in the liver and pancreatic β-cells. Recent study results have demonstrated that GK actually plays an important role for the maintenance of systemic glucose homeostasis, so that the hypothesis could be proved. For example, glucokinase gene deficient mice had significant hyperglycemic symptoms and died shortly after birth. In addition, in heterozygous GK knockout mice, glucose tolerance was deteriorated and glucose-stimulated insulin secretion was impaired. On the other hand, in normal mice in which GK was excessively expressed, the lowering of a blood glucose level, an increase in hepatic glycogen content, and the like were observed, and such phenomena were observed also in mice in which diabetes was artificially developed.
Furthermore, recent studies have revealed that GK functions as a glucose sensor and plays an important role for the maintenance of glucose homeostasis even in humans. An abnormality in the GK gene was found in a family line of maturity-onset diabetes of the young referred to as “MODY2,” and the correlation between the symptoms of this disease and GK activity was clarified (non-patent document 4). Meanwhile, a family line having mutagenesis for increasing GK activity was also found. In such a family line, fasting hypoglycemic symptoms attended with an increase in the plasma insulin level were also observed (non-patent document 5). From these reports, it is considered that GK functions as a glucose sensor in mammals including humans and plays an important role for regulation of blood glucose. Accordingly, it is considered that a substance having a GK-activating action is useful as an agent for glucose metabolism-related diseases including type II diabetes as a typical example. In particular, such a GK-activating substance can be expected to simultaneously have a glucose uptake-promoting action and a glucose production-suppressing action on the liver, and also an insulin secretion-promoting action on pancreatic β-cells. As such, it is anticipated that a GK-activating substance could provide strong therapeutic effects, which existing agents could not achieve. In recent years, it became clear that pancreatic β-cell-type GK is focally expressed in the ventromedial hypothalamus (VMH) of rat brain. It has previously been known that neurons that respond to glucose level are present in VMH. When glucose is administered into the cerebral ventricle of a rat, food intake is decreased. In contrast, when glucosamine as a glucose analog is administered into the cerebral ventricle of a rat to inhibit glucose metabolism, food intake is accelerated (non-patent document 6). As a result of an electrophysiological experiment, it has been known that glucose-responsive neurons are activated, responding to a change in physiological glucose levels (5 to 20 mM). It became clear that, during such activation, glucokinase functions as a glucose sensor, as with peripheral tissues (non-patent document 7). Therefore, a substance that activates glucokinase not only in the liver and pancreatic β-cells but also in VMH can be expected to act to correct obesity, which is a problem for many patients with type II diabetes, as well as acting to lower blood glucose level.
Based on the above descriptions, a substance having a GK-activating action is useful as an agent for treating and preventing diabetes, or as an agent for treating and preventing a chronic complication of diabetes, such as retinopathy, nephropathy, neuropathy, ischemic heart disease, or arteriosclerosis.
A glucokinase-activating agent is anticipated as a new type of diabetes-treating agent having two actions, namely, an insulin secretion-enhancing action in pancreatic β-cells and a glucose use-accelerating action in liver.
With regard to the compounds of the present invention having a spiroindoline skeleton, therapeutic agents for Alzheimer's disease (patent document 1 and patent document 2), a therapeutic agent for inflammatory disease (patent document 3), anticancer agents (patent document 4 and patent document 5), a diabetes-treating agent based on a 11β-HSD1 inhibitory activity (patent document 6), an insecticide (patent document 7), an antianxiety agent (non-patent document 8) and the like have been reported. However, all of these compounds are different from the compound of the present invention in terms of a substituent on a spiroindoline ring.